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Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at Original Research n Neuroradiology High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-weighted MR Images: Relationship with Increasing Cumulative Dose of a Gadoliniumbased Contrast Material 1 Tomonori Kanda, MD, PhD Kazunari Ishii, MD, PhD Hiroki Kawaguchi, MD Kazuhiro Kitajima, MD, PhD Daisuke Takenaka, MD, PhD 1 From the Department of Diagnostic Radiology, Hyogo Cancer Center, Akashi, Hyogo, Japan (T.K., H.K., D.T.); Department of Radiology, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan (K.I.); and Department of Radiology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan (K.K.). Received July 18, 2013; revision requested September 9; revision received October 9; accepted October 14; final version accepted November 13. Address correspondence to T.K., Department of Radiology, Teikyo University School of Medicine, Itabashi, Kaga, Itabashi-ku, Tokyo , Japan ( q RSNA, 2013 Purpose: Materials and Methods: Results: Conclusion: To explore any correlation between the number of previous gadolinium-based contrast material administrations and high signal intensity (SI) in the dentate nucleus and globus pallidus on unenhanced T1- weighted magnetic resonance (MR) images. The institutional review board approved this study, waiving the requirement to obtain written informed consent. A group of 381 consecutive patients who had undergone brain MR imaging was identified for cross-sectional analysis. For longitudinal analysis, 19 patients who had undergone at least six contrast-enhanced examinations were compared with 16 patients who had undergone at least six unenhanced examinations. The mean SIs of the dentate nucleus, pons, globus pallidus, and thalamus were measured on unenhanced T1-weighted images. The dentate nucleus to-pons SI ratio was calculated by dividing the SI in the dentate nucleus by that in the pons, and the globus pallidus to-thalamus SI ratio was calculated by dividing the SI in the globus pallidus by that in the thalamus. Stepwise regression analysis was undertaken in the consecutive patient group to detect any relationship between the dentate nucleus to-pons or globus pallidus to-thalamus SI ratio and previous gadolinium-based contrast material administration or other factors. A random coefficient model was used to evaluate for longitudinal analysis. The dentate nucleus to-pons SI ratio showed a significant correlation with the number of previous gadolinium-based contrast material administrations (P,.001; regression coefficient, 0.010; 95% confidence interval [CI]: 0.009, 0.011; standardized regression coefficient, 0.695). The globus pallidus to-thalamus SI ratio showed a significant correlation with the number of previous gadolinium-based contrast material administrations (P,.001; regression coefficient, 0.004; 95% CI: 0.002, 0.006; standardized regression coefficient, 0.288), radiation therapy (P =.009; regression coefficient,20.014; 95% CI: , ; standardized regression coefficient, ), and liver function (P =.031; regression coefficient, 0.023; 95% CI: 0.002, 0.044; standardized regression coefficient, 0.107). The dentate nucleus topons and globus pallidus to-thalamus SI ratios in patients who had undergone contrast-enhanced examinations were significantly greater than those of patients who had undergone unenhanced examinations (P,.001 for both). High SI in the dentate nucleus and globus pallidus on unenhanced T1-weighted images may be a consequence of the number of previous gadolinium-based contrast material administrations. q RSNA, radiology.rsna.org n Radiology: Volume 270: Number 3 March 2014 High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted magnetic resonance (MR) images is commonly observed. Previous studies have reported that high signal intensity in the dentate nucleus is associated with a history of brain irradiation or multiple sclerosis (1,2), whereas high signal intensity of the globus pallidus has been associated with hepatic dysfunction (3 5), Wilson disease (3,6), Rendu-Osler-Weber disease (7), manganese toxicity (8,9), calcification (8,10), hemodialysis (11), total parenteral nutrition (12), and neurofibromatosis type 1 (13). In our institution, we noticed that high signal intensity in the dentate nucleus and globus pallidus is also common in patients with a history of multiple administrations of gadolinium-based contrast material. In such patients, the signal intensity on T1-weighted images appears higher with increasing number of exposures to gadolinium-based contrast material. We hypothesized that high signal intensity of the dentate nucleus and globus pallidus on T1-weighted images was associated with previous gadolinium-based contrast material administration. The purpose of this study was to explore any correlation between the number of previous gadolinium-based contrast material administrations and high signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images. Advance in Knowledge nn High signal intensity of both the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images correlates with the number of previous gadoliniumbased contrast medium administrations (dentate nucleus: P,.001, regression coefficient = % confidence interval [CI]: 0.009, 0.011; globus pallidus: P,.001, regression coefficient = 0.004, 95% CI: 0.002, 0.006). Materials and Methods Patients Our institutional review board approved this study. The requirement to obtain written informed consent was waived because this was a retrospective study. All patients had given consent at the time of the examination to the use of their image data in research. We identified one patient group for cross-sectional analysis, with two subgroups for longitudinal analysis. Cross-sectional Analysis of the Patient Group From January 1, 2011, to February 28, 2011, 384 consecutive patients underwent brain MR imaging at our institution. Two patients did not undergo unenhanced T1-weighted imaging and were excluded from this study. One patient had a history of total parenteral nutrition containing manganese within the previous 6 months and was also excluded. The remaining 381 patients (mean age, 67.4 years; age range, years; 229 men, 152 women) were evaluated (consecutive patient group). Most patients (377 patients) had a history of neoplastic disease, and MR imaging was performed either to evaluate tumor size or to search for new metastases. None of the patients had a history of multiple sclerosis. None of the patients had nephrogenic systemic fibrosis. Contrast-enhanced Examination Subgroup From the consecutive patient group, we identified 102 patients who had undergone at least six contrast material enhanced MR examinations. Fiftythree patients were excluded because Implication for Patient Care nn High signal intensity in the globus pallidus and dentate nucleus may be present on unenhanced T1-weighted MR images in patients who have undergone a relatively large number of previous gadolinium-based contrast material administrations. the examinations were performed before digital images were routinely stored. An additional 30 patients were excluded because they had undergone brain radiation therapy, had a brain tumor, or had abnormal liver function (see below). The remaining 19 patients were assigned to the contrast-enhanced examination subgroup (mean age, 67.7 years; age range, years; 10 men, nine women). Unenhanced Examination Subgroup We identified 16 patients who had undergone at least six unenhanced examinations between May 1, 2006, and December 31, 2012 (range, 6 13 examinations; mean, 8.1 examinations). All patients had a history of lung cancer, and MR imaging was performed to detect brain metastases. None of the patients had a history of multiple sclerosis. These patients were classified as the unenhanced examination subgroup (mean age, 73.5 years; age range, years: six men, 10 women). Data Analysis We evaluated the sex and age of the patients, the number and type of previous gadolinium-based contrast material administrations, whether the patients had a history of radiation therapy or chemotherapy, the site of any tumor, and the patient s hepatic and renal function. Radiation therapy was defined as a history of radiation therapy to the brain Published online before print /radiol Content code: Radiology 2014; 270: Abbreviations: CI = confidence interval egfr = estimated glomerular filtration rate ROI = region of interest Author contributions: Guarantors of integrity of entire study, T.K., K.I., D.T.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, T.K.; clinical studies, T.K., H.K., D.T.; statistical analysis, T.K., K.I., K.K.; and manuscript editing, T.K., K.I., K.K., D.T. Conflicts of interest are listed at the end of this article. Radiology: Volume 270: Number 3 March 2014 n radiology.rsna.org 835 and was classified as gamma knife or other tumor-selective radiation therapy that excluded the globus pallidus and dentate nucleus from the radiation field (grade 1) or whole-brain irradiation (grade 2). A tumor was considered to be present anywhere in body if it was evident on the brain MR images or if a tumor had recurred anywhere in the body at a 1-year follow-up study. A brain tumor was considered to be present if primary or secondary brain tumors were detected on MR images. Patients were also grouped according to a history of chemotherapy, which was further classified according to the previous administration of molecularly targeted therapy or platinum-based chemotherapy. Abnormal liver function was defined by abnormal serum concentrations of aspartate aminotransferase, alanine aminotransferase, total bilirubin, or g-glutamyl transpeptidase. Renal function was evaluated by calculating the estimated glomerular filtration rate (egfr) from a recent blood sample and was classified as follows: normal (egfr. 60 ml/min/m 2 ), moderately abnormal (egfr between 30 and 60 ml/min/m 2 ), or severe insufficiency (egfr, 30 ml/min/m 2 ). The number of previous gadolinium-based contrast material administrations was defined as the number of previous contrast-enhanced MR examinations performed at our center. At our institution, 7.5 mmol of gadopentetate dimeglumine (Magnevist; Bayer Yakuhin, Osaka, Japan) or gadodiamide (Omniscan; Daichi Sankyo, Tokyo, Japan) was used for adult patients in every contrast-enhanced MR study. Imaging and Data Analysis Whole-brain MR imaging was performed with one of two 1.5-T MR imaging units (Signa HDxt or Signa Excite Twin Speed; GE Medical Systems, Tokyo, Japan). Axial unenhanced T1-weighted images were obtained with the following parameters: repetition time msec/echo time msec, /9; section thickness, 5 mm; number of signals acquired, two; and matrix size, Axial T2-weighted images were obtained Figure 1 Figure 1: MR images in 45-year-old woman with glioblastoma treated with surgery, chemotherapy, and radiation therapy. (a) Unenhanced T1-weighted image shows high-signal-intensity globus pallidus. Standard ROIs were placed around globus pallidus and thalamus. (b) Fast spin-echo T2-weighted image at same level as a. (c) Unenhanced T1-weighted image shows high-signal-intensity dentate nucleus. Standard ROIs were placed around dentate nucleus and pons. (d) Fast spin-echo T2-weighted image at same level as c. with the following parameters: /90; section thickness, 5 mm; number of signals acquired, two; matrix size, ; and echo train length, Quantitative analysis was conducted by two radiologists (T.K. and H.K., with 10 and 4 years of experience, respectively), who were blinded to the clinical data, by using the unenhanced T1-weighted images with operatordefined region-of-interest (ROI) measurements of mean signal intensity. Oval ROIs were placed around the right dentate nucleus, central pons, right globus pallidus, and right thalamus. If the right side could not be assessed because of pulsation artifact, metal artifact, or brain necrosis, the left side was used. If the dentate nucleus, globus pallidus, or thalamus was unclear on T1-weighted images, the same section position on T2-weighted images was used to guide ROI placement. Correct ROI placement was agreed on by consensus, and ROI measurement was conducted once (see Fig 1 for examples). The dentate nucleus to-pons signal intensity ratio was calculated by dividing the mean 836 radiology.rsna.org n Radiology: Volume 270: Number 3 March 2014 signal intensity of the dentate nucleus by that of the central pons. The globus pallidus to-thalamus signal intensity ratio was calculated by dividing the mean signal intensity of the globus pallidus by that of the thalamus. The last examination of each patient from the large consecutive patient group and the first and last examinations of the contrast-enhanced and unenhanced examination subgroups were analyzed. Statistical Analysis Stepwise regression analysis was performed with software (PASW Statistics, version 21.0; SPSS, Chicago, Ill) to evaluate the relationships between the dentate nucleus to-pons or globus pallidus to-thalamus ratios and the following factors: sex, age, liver function, renal function, tumor anywhere in the body, brain tumor, number of previous gadolinium-based contrast material administrations, radiation therapy, chemotherapy, platinum-based chemotherapy, and molecularly targeted therapy. A random coefficient model was used to evaluate changes in the dentate nucleus to-pons or globus pallidus to-thalamus ratios in the contrastenhanced and unenhanced examination subgroups. The model was defined as follows: Y jkl = b 0 + (b 1 + a j ) t k + b 2 l + b 3 l t k, where Y is the signal intensity, l is the subgroup factor (contrast-enhanced examination group: l = 0, unenhanced examination group: l = 1), t k is the time elapsed between the first and last examination (first examination: k = 1, last examination: k = 2), and b 0, b 1, b 2, and b 3 are the fixed effects and a j is the random effect for each patient. The parameters of each model were calculated with restricted maximum likelihood. The paired t test was used to evaluate the signal changes in dentate nucleus to-pons and globus pallidus to-thalamus ratios in both subgroups. The random coefficient models were built and analyzed by using the R software environment for statistical computing (version 3.0.1; P,.05 was considered indicative of a statistically significant difference. Table 1 Summary of Patient Characteristics Parameter Results Consecutive Patient Group (n = 381) The number of previous gadoliniumbased contrast material administrations in the consecutive patient group ranged from zero to 30 (mean, 3.57). The contrast-enhanced examination subgroup had undergone six to 12 examinations (mean, 7.1 examinations). In the consecutive patient group, 31 of the 381 patients (8.1%) had undergone whole-brain irradiation, 46 (12.0%) had undergone gamma knife or other tumor-selective radiation therapy that excluded the globus pallidus and dentate nucleus from the field, 222 (58.3%) had tumors anywhere in the body, 104 (27.3%) had at least one brain tumor, 200 (52.5%) had undergone chemotherapy, 134 (35.2%) had undergone platinumbased chemotherapy, 48 (12.6%) had undergone molecularly targeted therapy, 30 (7.9%) had abnormal liver function, 36 (9.5%) had moderately abnormal renal function, and two (0.5%) had severe renal insufficiency. The characteristics of each group are outlined in Table 1. Contrast-enhanced Examination Subgroup (n = 19) Unenhanced Examination Subgroup (n = 16) Age (y)* Sex M F Brain radiation therapy Whole brain Partial or gamma knife Tumor anywhere in body Brain tumor Chemotherapy Platinum-based chemotherapy Molecularly targeted therapy Abnormal liver function Abnormal renal function egfr between 30 and 60 ml/min/m egfr, 30 ml/min/m Note. Except where indicated, data are numbers of patients. * Data are means 6 standard deviations. Scatterplots of the dentate nucleus to-pons and globus pallidus to-thalamus ratios according to number of previous gadolinium-based contrast material administrations are shown in Figure 2 and indicate a positive correlation between the number of previous gadoliniumbased contrast material administrations and the dentate nucleus to-pons ratio. Results of stepwise regression analysis are shown in Table 2. In all steps of the stepwise regression analysis, the dentate nucleus to-pons signal intensity ratio showed a significant correlation only with the number of previous gadolinium-based contrast material administrations (P,.001; regression coefficient, 0.010; 95% confidence interval [CI]: 0.009, 0.011; standardized regression coefficient, 0.695). The globus pallidus to-thalamus signal intensity ratio showed a significant correlation with the number of previous gadoliniumbased contrast material administrations in all steps of the stepwise regression analysis (P,.001; regression coefficient, 0.004; 95% CI: 0.002, 0.006; standardized regression coefficient, 0.288). In the final steps of the stepwise Radiology: Volume 270: Number 3 March 2014 n radiology.rsna.org 837 Figure 2 Figure 2: (a) Scatterplot of dentate nucleus to-pons signal intensity ratio versus number of previous gadolinium-based contrast material administrations. (b) Scatterplot of globus pallidus to-thalamus signal intensity ratio versus number of previous gadolinium-based contrast material administrations. In each plot, solid line represents linear regression and dashed lines indicate 95% confidence limits. regression analysis, radiation therapy showed a significant negative correlation (P =.009; regression coefficient, ; 95% CI: , ; standardized regression coefficient, ) and liver function showed a significant positive correlation (P =.031; regression coefficient, 0.023; 95% CI: 0.002, 0.044; standardized regression coefficient, 0.107) with the globus pallidus to-thalamus signal intensity ratio. The globus pallidus to-thalamus ratio was more strongly influenced by the number of previous gadolinium-based contrast material administrations than by radiation therapy or liver function. Scatterplots of changes in the dentate nucleus to-pons and globus pallidus to-thalamus signal intensity ratio in the contrast-enhanced and unenhanced examination subgroups are shown in Figure 3. The dentate nucleus to-pons and globus pallidus tothalamus signal intensity ratios in the contrast-enhanced examination subgroup exhibited increased signal intensity compared with that of the unenhanced subgroup over time. Table 3 shows the estimated fixed effects of a repeat measure linear mixed model. The time 3 subgroup factors of the dentate nucleus to-pons ( ; standard error, ) and globus pallidus to-thalamus ( ; standard error ) signal intensity ratio were significant (P,.001 for both). For patients in the contrast-enhanced examination subgroup (l = 0), the coefficient of the time factor was b 1 and was for the dentate nucleus topons signal intensity ratio and for the globus pallidus to-thalamus signal intensity ratio; signal intensity increased over time. For patients in the unenhanced examination subgroup (l = 1), the coefficient of the time factor was b 1 b 3 and was for the dentate nucleus to-pons signal intensity ratio and for the globus pallidus to-thalamus signal intensity ratio; signal intensity change was minimal. Discussion Our study revealed a correlation between a high-signal-intensity dentate nucleus and globus pallidus on T1- weighted images in patients with a history of gadolinium-based contrast material administration independent of renal function. To our knowledge, M

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